Disease-causing
genes are searched for by researchers, and the resulting genetic
tests are desired by breeders. Once obtained, it is a double-edged
sword: Its use can enable breeders to improve a breed or devastate it.

Most dog and cat
breeds have a closed stud book, which means that there is a finite
amount of polymorphic genes and genetic diversity present. They can
only lose genes, not gain them through selective breeding.

The primary
reaction of a breeder discovering that their breeding stock carries a
defective gene is to retire it from breeding. As researchers, we
often recommend using a genetic test to eliminate carriers from breeding.

Widespread
elimination of all carriers of a high frequency gene can place a
strong negative pressure on a gene pool. This can act to decrease the
genetic diversity of the breed, cause a loss of other quality genes,
and increase the frequency of other defective genes through genetic bottlenecks.

We know that most
individuals carry some unfavorable genes. The more genetic tests that
are developed, the greater chance that a breeder will identify an
undesirable gene in their breeding stock. Making breeding decisions
based on a single testable gene is inappropriate. Any quality
individual that would have been bred if it had tested normal should
still be bred if it tests as a carrier.

Prospective
breeding animals represent the quality of the gene pool. A genetic
test that was designed to help a breed and its gene pool should not
be used to devastate it. As more genetic tests are developed, the
discarding of individuals based on single, testable genes further
restricts the gene pool. We should be offering genetic counseling
recommendations that eliminates defective genes, but maintains breed
lines and genetic diversity.

The best way to
utilize genetic tests is to breed quality carriers to normal-testing
mates, and replace them with quality, non-carrier offspring. This
prevents affected offspring, while maintaining breed lines and
genetic diversity in the breed.

Genetic
Counseling and Control of Genetic Disease

The primary goal
of domestic animal breeding is to maintain and enhance the quality of
the breed. This is well understood in livestock production breeding,
but often overlooked in dog and cat breeding. Breeders must consider
all relevant aspects, which may include various health issues,
conformation, temperament, and working ability. Health and diversity
issues are important, but they must coincide with, and not replace
selection for quality.

The goals of
genetic counseling are to:

Prevent the
production of additional affected individuals

Decrease the
frequency of the defective gene(s)

Maintain a
genetically diverse pure-bred population

Genetic counseling
recommendations need to take into account the dynamics and
epidemiology of both the breed gene pool, and the defective gene(s).
Rare or low frequency defective genes require more stringent
selective pressure to prevent their spread. High frequency
(breed-wide) defective genes require more pragmatic management that
does not adversely affect the gene pool.

Historical Examples

At the onset of
testing for the autosomal recessive gene for GM1-gangliosidosis in
the Portuguese Water Dog, the carrier frequency was 16%. The breed in
America originated from less than ten individuals imported in the
late 1960s and early 1970s. The defective gene was brought into the
breed by the ancestral Algarbiorum line, which was the dominant
breeding line. Breeders recognized that the Alvalade line did not
carry the defective gene for GM-1 gangliosidosis, and preferentially
selected dogs from this line for breeding, making it the major
influence in the breed. Unfortunately, the Alvalade line carried the
gene for late-onset prcd-PRA, including several influential affected
imports. This defective gene was not present in the Algarbiorum line.
The end result of selection was the near elimination of one ancestral
line, and a breed-wide carrier frequency of prcd-PRA of 35%.

In cat breeds,
genetic testing for the autosomal dominant genes for polycystic
kidney disease in Persian and Himalayan cats (38% affected worldwide)
and hypertrophic cardiomyopathy in Maine Coon Cats (over 30% affected
worldwide) will require careful selection to maintain breed
diversity. Obviously, breeders do not want to produce additional
affected cats. However, the wide scale elimination of over 30% of the
breed would put a significant negative pressure on the gene
pool--even in these populous breeds. The amount of quality genes and
quality cats that can be lost forever from such selection, and the
amount of genetic bottlenecking could be devastating. Concurrently
preserving the diversity of the gene pool over the next few
generations while at the same time eliminating the defective gene is
the most practical and desirable way to manage the disorders.

The American
Burmese cat breed in recent years has split into a traditional and a
contemporary head phenotype. Unfortunately, the contemporary
phenotype that has been desired in the show ring is shown to be
caused by the heterozygous genotype for the recessive, lethal,
cranio-facial defect. Dr. Leslie Lyon's laboratory at UC-Davis is in
the process of identifying the defective gene. Once a genetic test is
established, it will be seen how the breeders will utilize the test
for the best interests of the breed.

Genetic
Counseling Recommendations

Selection against
a single gene trait with a test for carriers is based on the
individual. Breeders only have to know the results of the individuals
they plan on breeding.

Selection against;
disorders that lack a test for carriers, complexly inherited
disorders, or disorders with an unknown mode of inheritance, require
knowledge of the carrier or affected status of related animals.

Autosomal
Recessive Disorders

With a valid
genetic test for carriers, breeders should mate quality carriers to
normal-testing individuals, and replace the carrier parent with a
quality, normal-testing offspring. Carrier-testing offspring should
be selected against for breeding. In this way breeders can prevent
affected offspring, while eliminating the defective gene from their
breeding stock in one generation.

Without a genetic
test for carriers, knowledge of the affected or carrier status of
relatives is important. This requires testing for the affected
phenotype, knowledge of pedigree backgrounds, and relative risk
pedigree analysis. An open health database is the best method for
objectively disseminating this information. Breeders should mate
quality, higher-risk individuals to lower-risk individuals. Replace
the higher-risk individuals with their lower-risk offspring. Repeat
the process in the next generation. If the majority of breeders plan
matings with a carrier-risk below the average of the breed, then the
frequency of the defective gene will diminish in the population. This
has been successfully done in many breeds.

Relative Risk
Pedigree Analysis

With simple
autosomal recessive genes and no test for carriers, knowledge of
affected and carrier relatives can provide an objective risk
assessment. Relative risk is the minimal risk based on known risk
from the pedigree. The following are obligate carrier risk values:
Offspring of affected = 100%, Parent of affected = 100%,
Phenotypically normal full-sib to affected = 67%, Full-sib to carrier
= 50%.

If risk comes down
from only one parent, then the offspring's carrier risk is half that
of the parent. If risk comes down from both parents, then the
affected risk is half the sire's risk times half the dam's risk.

S = risk of being
carrier from the Sire.

D = risk of being
carrier from the Dam.

Risk of being
affected = S x D

The carrier risk
depends on the knowledge of whether the individual can be excluded as
phenotypically affected.

If you do not know
if the individual is phenotypically normal or affected, then the risk
of being a carrier is the sum of the risk from both parents, minus
the risk of being affected.

If affected
individuals cannot reproduce, or it is known that the individual is
not phenotypically affected, then:

Pros: Relative
risk pedigree analysis objectifies risk relative to the population.
It allows breeders to understand their own risk, and that of their
proposed matings. It allows breeders with higher-risk breeding stock
to lower their risk through planned matings.

Cons: Relative
risk pedigree analysis selects against entire families, based on
relatives with risk. It selects against both carrier and normal
individuals. However, without carrier tests it is an effective tool
to reduce the frequency of both affected and carrier individuals, and
has been successfully used in many breeds.

X-linked
(Sex-Linked) Recessive Disorders

Replacing affected
and carrier individuals with normal male relatives will lose the
defective gene in one generation. Avoid breeding high carrier-risk
females, as half of the male offspring from carrier females will be affected.

Autosomal
Dominant and X-linked Dominant Disorders

Quality affected
individuals should be replaced for breeding with a normal-testing
parent, sibling, or prior-born offspring. Ideally you do not want to
breed affected individuals, as half of their offspring will be affected.

Complexly
Inherited (Polygenic) Disorders, and Familial Disorders With No Known
Mode of Inheritance

The knowledge of
affected relatives is important in determining risk status. Open
health database registries can provide this important information.
Three factors should be considered:

Complexly
inherited disorders should be viewed as threshold traits. A number of
genes must combine to cross a threshold to produce an affected individual.

Icreased response
to selection can be attained by attempting to break down the
phenotype into measurable traits that may be more directly linked to
the underlying genes. Example: Measuring joint laxity, acetabular
depth, or liability to secondary boney changes in hip dysplasia.

The most important
method to manage complexly inherited disorders is to select for
breadth of pedigree normalcy. Phenotypically normal individuals with
normal or mostly normal littermates have the greatest chance of
carrying normal genes. Phenotypically normal individuals with
affected littermates have a greater chance of carrying a genetic load
of disease-causing genes. Normal parents who have a preponderance of
normal littermates provides even greater confidence.

An open health
database that shows genetic test results of close relatives can
provide this information.

Genetic tests are
powerful tools, and as with any tool require an instruction manual
for their proper use. When offering these tests to breeders, we need
to provide genetic counseling advice that allows their use to be
beneficial, and not detrimental to the breeds.